Cancer of the lung and bronchus (lung cancer) is the second most common cancer among both men and women and is the leading cause of cancer death in both sexes. Among men, age-adjusted lung cancer incidence rates (per 100,000) range from a low of about 14 to a high of 117, an eight- fold difference, depending upon ethnicity. The rates among men are about two to three times greater than the rates among women in each of the racial/ethnic groups.
Leukemia and lymphoma are the most common fatal cancers in young men under age 39. Leukemia, Hodgkin and non-Hodgkin lymphoma and myeloma are cancers that originate in the bone marrow or lymphatic tissues. An estimated 106,300 people in the United States will be diagnosed with leukemia, lymphoma or myeloma in 2002. New cases of leukemia, Hodgkin and non-Hodgkin lymphoma and myeloma account for 8.3 percent of the 1,284,900 new cancer cases diagnosed in the United States this year. See Surveillance, Epidemiology and End Results (SEER) Program 1979-1998, National Cancer Institute; American Cancer Society.
An estimated 616,695 Americans are currently living with leukemia, Hodgkin and non-Hodgkin lymphoma and myeloma. Leukemia, lymphoma and myeloma will cause the deaths of an estimated 58,300 people in the United States this year. These blood cancers will account for nearly 10.5 percent of the deaths from cancer in 2002 based on the total of 555,500 cancer-related deaths (all sites).
The short chain dehydrogenase/reductase (SDR) family of NAD(P)(H) dependent oxido-reductases are believed to have a role in disease, for example, cancer, inflammatory disease, and diabetes. The SDR family represents a diverse family of >63 human proteins (Oppermann, U. C., et al., Chem Biol Interact, 130-132: 699-705, 2001. Kallberg, Y., et al., Eur J Biochem, 269: 4409-17, 2002. Kallberg, Y., et al., Protein Sci, 11: 636-41, 2002). These enzymes are responsible for the oxidation or reduction of a wide range of endogenous (prostaglandins, steroid hormones, retinal, dihydropteridin, UDP, and trans 2-enoyl CoA) and exogenous chemicals (anthracyclin drugs, quininones, and others). The SDR family members thus control the cell specific production/destruction of potent hormones as well as the detoxification of important classes of drugs such as the anti-cancer agent adriamycin (Forrest, G. L. et al., Chem Biol Interact, 129: 21-40, 2000).
Carbonyl reductase (CBR) (NADPH: secondary-alcohol oxidoreductase) is part of a group of NADPH-dependent cytosolic enzymes called short chain dehydrogenase/reductase (SDR) that catalyze the reduction of various carbonyl compounds to their corresponding alcohols. The enzyme is ubiquitous in nature and acts on a large number of biologically and pharmacologically active compounds. Carbonyl reductase is believed to function physiologically as a dehydrogenase or reductase of prostaglandins or hydroxysteroids, as well as in drug metabolism.
Carbonyl reductase is primarily monomeric in structure, and has been characterized in humans from placenta, liver, and breast tissue. CBR bears a low overall degree of homology (24-36%) with other SDR enzymes from mammalian sources such as mouse and pig (Nakanishi, M. et al. Biochem. Biophys. Acta 194: 1311-16, 193). However, all of these enzymes are linked by two common consensus sequences; the sequence TGxxxGxG, found in the N-terminal portion of the molecule and responsible for binding the NADPH co-enzyme, and the sequence YxxxK, located close to the C-terminal end of the molecule, and active in carbonyl reduction. Differences in amino acid sequences between these enzymes can be responsible, in part, for differences in their respective substrate specificities for various carbonyl compounds.
The bioreduction of prostaglandin (PGE) by carbonyl reductase serves to regulate cellular levels of PGE. A wide variety of biological activities are ascribed to PGEs including smooth muscle contraction, platelet aggregation, inflammation, inhibition of insulin secretion, and lymphocyte function. Excessive PGE production is associated with inflammatory diseases, diabetes, and suppression of the immune response. Inhibitors of PGE biosynthesis, such as indomethacin and ibuprofen, are commonly used to treat inflammation and inflammatory diseases and depressed cellular immunity in patients with conditions such as Hodgkin's disease (Isselbacher K. J. et al. Harrison's Principles of Internal Medicine, Vol. 1: 431-435, 1994, McGraw-Hill, New York City).
In human liver, carbonyl reductase also reduces quinones, an important class of mutagens and carcinogens, and appears to be the principle mechanism for detoxification of these compounds. CBR production is stimulated by carcinogens such as butyl hydroxyanisole and beta-naphthoflavone that also induce other cancer-protective enzymes (Forrest, G. L. et al. Biochim. Biophys. Acta 1048: 149-55, 1990).
Human carbonyl reductase 1 (CBR1) has been characterized as having similarity to carbonyl reductases from porcine lung (GI 416425), mouse adipocytes (GI 50004), and human liver (GI 118519). Human CBR1 is 85% identical to porcine carbonyl reductase. The role of carbonyl reductase in cells is not understood.
Carbonyl reductase is also involved in the metabolism of anthracyclines, a widely used class of anticancer chemotherapeutic drugs. Daunorubicin (DNR) and Doxorubicin (DXR), the two principle anthracyclines used in cancer chemotherapy, are reduced to their respective alcohols by carbonyl reductase. The alcohol products are much less effective antitumor agents than the parent compounds. In fact, increased carbonyl reductase levels associated with some anthracycline resistant tumors suggest that increased carbonyl reductase activity may be responsible for drug resistance in these cells (Soldan, M. et al. Biochem. Pharmacol. 51: 116-23, 1996; Gonzalez, B. et al. Cancer Res. 55: 4646-50, 1995). Another problem of anthracyclines is cardiotoxicity, but the causative agents are suggested to be the alcohol products of carbonyl reductase catalyzed reaction. (Forrest, G. L. et al., Chem Biol Interact, 129: 21-40, 2000.)
Daunorubicin is one of the family of anthracycline antibiotic drugs that include daunorubicin, doxorubicin, epirubicin, and idarubicin. These drugs are used in the treatment of acute leukemia, lymphomas, and myeloma. Daunorubicin is used to treat acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, neuroblastoma. Liposomal daunorubicin belongs to the general group of medicines known as antineoplastics. It is used to treat advanced acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS),
Molecules that inhibit short chain dehydrogenase/reductase (SDR) family of NAD(P)(H) dependent oxido-reductases, for example, carbonyl reductase, satisfy a need in the art by providing new diagnostic or therapeutic compositions useful in the prevention and treatment of inflammation, immunological disorders, cancer, and drug resistance in cancerous cells, and reducing toxicity associated with CBR catalyzed metabolites of known drugs.